CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Current Address: Department of Neurobiology, Care Science and Society, Karolinska Institutet, Stockholm, Sweden.
CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Free Radic Biol Med. 2021 Feb 1;163:163-179. doi: 10.1016/j.freeradbiomed.2020.11.031. Epub 2020 Dec 4.
SIRT3 is a major regulator of mitochondrial acetylome. Here we show that SIRT3 is neuroprotective in Huntington's disease (HD), a motor neurodegenerative disorder caused by an abnormal expansion of polyglutamines in the huntingtin protein (HTT). Protein and enzymatic analysis revealed that increased SIRT3 is a signature in several HD models, including human HD brain, which is regulated by oxidative species. While loss of SIRT3 further aggravated the oxidative phenotype, antioxidant treatment regularized SIRT3 levels. SIRT3 overexpression promoted the antioxidant effect in cells expressing mutant HTT, leading to enhanced mitochondrial function and balanced dynamics. Decreased Fis1 and Drp1 accumulation in mitochondria induced by SIRT3 expression favored mitochondrial elongation, while the SIRT3 activator ε-viniferin improved anterograde mitochondrial neurite transport, sustaining cell survival. Notably, SIRT3 fly-ortholog dSirt2 overexpression in HD flies ameliorated neurodegeneration and extended lifespan. These findings provide a link between oxidative stress and mitochondrial dysfunction hypotheses in HD and offer an opportunity for therapeutic development.
SIRT3 是线粒体乙酰基组的主要调节因子。在这里，我们表明 SIRT3 在亨廷顿病（HD）中具有神经保护作用，HD 是一种由亨廷顿蛋白（HTT）中异常扩展的多聚谷氨酰胺引起的运动神经退行性疾病。蛋白质和酶分析显示，几种 HD 模型中 SIRT3 的增加是一个特征，包括人类 HD 大脑，其受氧化物种调节。虽然 SIRT3 的缺失进一步加重了氧化表型，但抗氧化剂治疗使 SIRT3 水平正常化。SIRT3 的过表达促进了表达突变 HTT 的细胞中的抗氧化作用，导致线粒体功能增强和动态平衡。SIRT3 表达诱导的 Fis1 和 Drp1 在线粒体中的积累减少有利于线粒体伸长，而 SIRT3 激活剂 ε-viniferin 改善了顺行线粒体神经突运输，维持了细胞存活。值得注意的是，HD 果蝇中 SIRT3 同源物 dSirt2 的过表达改善了神经退行性变并延长了寿命。这些发现为 HD 中的氧化应激和线粒体功能障碍假说提供了联系，并为治疗开发提供了机会。
